Baseline Asymptomatic Malaria Infection and Immunogenicity of Recombinant Vesicular Stomatitis Virus-Zaire Ebola Virus Envelope Glycoprotein.

BACKGROUND: The effect of malaria infection on the immunogenicity of the recombinant vesicular stomatitis virus-Zaire Ebola virus envelope glycoprotein (GP) vaccine (rVSVΔG-ZEBOV-GP) (ERVEBO) is unknown. METHODS: The Sierra Leone Trial to Introduce a Vaccine Against Ebola (STRIVE) vaccinated 7998 asymptomatic adults with rVSVΔG-ZEBOV-GP during the 2014-2016 Ebola epidemic. In STRIVE's immunogenicity substudy, participants provided blood samples at baseline and at 1, 6, and 9-12 months. Anti-GP binding and neutralizing antibodies were measured using validated assays. Baseline samples were tested for malaria parasites by polymerase chain reaction. RESULTS: Overall, 506 participants enrolled in the immunogenicity substudy and had ≥1 postvaccination antibody titer. Of 499 participants with a result, baseline malaria parasitemia was detected in 73 (14.6%). All GP enzyme-linked immunosorbent assay (ELISA) and plaque reduction neutralization test (PRNT) geometric mean titers (GMTs) at 1, 6, and 9-12 months were above baseline, and 94.1% of participants showed seroresponse by GP-ELISA (≥2-fold rise and ≥200 ELISA units/mL), while 81.5% showed seroresponse by PRNT (≥4-fold rise) at ≥1 postvaccination assessment. In participants with baseline malaria parasitemia, the PRNT seroresponse proportion was lower, while PRNT GMTs and GP-ELISA seroresponse and GMTs showed a trend toward lower responses at 6 and 9-12 months. CONCLUSION: Asymptomatic adults with or without malaria parasitemia had robust immune responses to rVSVΔG-ZEBOV-GP, persisting for 9-12 months. Responses in those with malaria parasitemia were somewhat lower.

Pregnancy Outcomes among Women Receiving rVSVΔ-ZEBOV-GP Ebola Vaccine during the Sierra Leone Trial to Introduce a Vaccine against Ebola.

Little information exists regarding Ebola vaccine rVSVΔG-ZEBOV-GP and pregnancy. The Sierra Leone Trial to Introduce a Vaccine against Ebola (STRIVE) randomized participants without blinding to immediate or deferred (18-24 weeks postenrollment) vaccination. Pregnancy was an exclusion criterion, but 84 women were inadvertently vaccinated in early pregnancy or became pregnant <60 days after vaccination or enrollment. Among immediate vaccinated women, 45% (14/31) reported pregnancy loss, compared with 33% (11/33) of unvaccinated women with contemporaneous pregnancies (relative risk 1.35, 95% CI 0.73-2.52). Pregnancy loss was similar among women with higher risk for vaccine viremia (conception before or <14 days after vaccination) (44% [4/9]) and women with lower risk (conception >15 days after vaccination) (45% [10/22]). No congenital anomalies were detected among 44 live-born infants examined. These data highlight the need for Ebola vaccination decisions to balance the possible risk for an adverse pregnancy outcome with the risk for Ebola exposure.

Health Conditions in an Adult Population in Sierra Leone: Data Reported From the Sierra Leone Trial to Introduce a Vaccine Against Ebola (STRIVE).

Clinical Trials Registration: ClinicalTrials.gov [NCT02378753] and Pan African Clinical Trials Registry [PACTR201502001037220].

Implementing a Multisite Clinical Trial in the Midst of an Ebola Outbreak: Lessons Learned From the Sierra Leone Trial to Introduce a Vaccine Against Ebola.

The Sierra Leone Trial to Introduce a Vaccine against Ebola (STRIVE), a phase 2/3 trial of investigational rVSV∆G-ZEBOV-GP vaccine, was conducted during an unprecedented Ebola epidemic. More than 8600 eligible healthcare and frontline response workers were individually randomized to immediate (within 7 days) or deferred (within 18-24 weeks) vaccination and followed for 6 months after vaccination for serious adverse events and Ebola virus infection. Key challenges included limited infrastructure to support trial activities, unreliable electricity, and staff with limited clinical trial experience. Study staff made substantial infrastructure investments, including renovation of enrollment sites, laboratories, and government cold chain facilities, and imported equipment to store and transport vaccine at ≤-60oC. STRIVE built capacity by providing didactic and practical research training to >350 staff, which was reinforced with daily review and feedback meetings. The operational challenges of safety follow-up were addressed by issuing mobile telephones to participants, making home visits, and establishing a nurse triage hotline. Before the Ebola outbreak, Sierra Leone had limited infrastructure and staff to conduct clinical trials. Without interfering with the outbreak response, STRIVE responded to an urgent need and helped build this capacity. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov [NCT02378753] and Pan African Clinical Trials Registry [PACTR201502001037220].

The Sierra Leone Trial to Introduce a Vaccine Against Ebola: An Evaluation of rVSV∆G-ZEBOV-GP Vaccine Tolerability and Safety During the West Africa Ebola Outbreak.

Clinical Trials Registration: ClinicalTrials.gov [NCT02378753] and Pan African Clinical Trials Registry [PACTR201502001037220].

Operationalizing International Regulatory Standards in a Limited-Resource Setting During an Epidemic: The Sierra Leone Trial to Introduce a Vaccine Against Ebola (STRIVE) Experience.

Clinical Trials Registration: ClinicalTrials.gov [NCT02378753] and Pan African Clinical Trials Registry [PACTR201502001037220].

Prevalence and risk factors associated with STIs among women initiating contraceptive implants in Kingston, Jamaica.

BACKGROUND: There is limited information on rates of STIs in Jamaica due to syndromic management and limited aetiological surveillance. We examined the prevalence of Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and Trichomonas vaginalis (TV) and characteristics associated with STIs among sexually active women who participated in a randomised trial of a progestin implant initiation in Jamaica (the Sino-Implant Study (SIS)). METHODS: SIS was a randomised trial conducted in Kingston, Jamaica, from 2012 to 2014 to evaluate whether initiation of the Sino-Implant (II) led to more unprotected sex among women ages 18-44 years. Data collected included self-reported demographic, sexual behaviour information; and vaginal swabs collected at baseline, 1-month and 3-month follow-up visits for a biomarker of recent semen exposure (prostate-specific antigen (PSA)) and for STIs. We examined associations between STIs and PSA, demographics, sexual behaviour and insertion of an implant, with a repeated-measures analysis using generalised estimating equations (SAS Institute, V.9.3). RESULTS: Remnant vaginal swabs from 254 of 414 study participants were tested for STIs. At baseline, 29% of participants tested for STIs (n=247) had laboratory-confirmed CT, 5% NG, 23% TV and 45% any STI. In a repeated-measures analysis adjusted for study arm (immediate vs delayed implant insertion), those with PSA detected did not have an increased prevalence of any STI (prevalence ratio (PR)=1.04 (95% CI 0.89 to 1.21)), whereas prevalence decreased for each 1-year increase in age (PR=0.98 (95% CI 0.97 to 0.99)). Immediate implant insertion was not associated with increases in any STI in subsequent visits (PR=1.09 (95% CI 0.94 to 1.27)). CONCLUSIONS: Although the prevalence of laboratory-confirmed STIs was high, the immediate initiation of a contraceptive implant was not associated with higher STI prevalence rates over 3 months. TRIAL REGISTRATION NUMBER: NCT01684358.

Sexual Relationship Power and Semen Exposure Among Female Patients at a Sexually Transmitted Infection Clinic in Kingston, Jamaica.

Women's power in sexual relationships is thought to be an important predictor of condom use. However, research on correlates of condom use often relies on participant reporting of behavior, which has questionable validity. We evaluated the association between scores from the modified Sexual Relationship Power Scale (SRPS-M) and biological detection of semen exposure in a prospective study of adult women attending a sexually transmitted infection clinic in Kingston, Jamaica with cervicitis or abnormal vaginal discharge in 2010-2011. At enrollment, women were counseled to avoid sex while on treatment and were asked to return in 6 days for a follow-up visit. At both study visits, women were administered a questionnaire and had vaginal swabs collected to test for prostate-specific antigen (PSA), a biological marker of recent semen exposure. We found no significant association at enrollment or follow-up between SRPS-M scores and semen exposure, as measured with either self-reported data or PSA positivity. Semen biomarkers could be used to develop and validate new scales on relationship power and self-efficacy related to condom use.

Implementing an Ebola Vaccine Study - Sierra Leone.

In October 2014, the College of Medicine and Allied Health Sciences of the University of Sierra Leone, the Sierra Leone Ministry of Health and Sanitation, and CDC joined the global effort to accelerate assessment and availability of candidate Ebola vaccines and began planning for the Sierra Leone Trial to Introduce a Vaccine against Ebola (STRIVE). STRIVE was an individually randomized controlled phase II/III trial to evaluate efficacy, immunogenicity, and safety of the recombinant vesicular stomatitis virus Ebola vaccine (rVSV-ZEBOV). The study population was health care and frontline workers in select chiefdoms of the five most affected districts in Sierra Leone. Participants were randomized to receive a single intramuscular dose of rVSV-ZEBOV at enrollment or to receive a single intramuscular dose 18-24 weeks after enrollment. All participants were followed up monthly until 6 months after vaccination. Two substudies separately assessed detailed reactogenicity over 1 month and immunogenicity over 12 months. During the 5 months before the trial, STRIVE and partners built a research platform in Sierra Leone comprising participant follow-up sites, cold chain, reliable power supply, and vaccination clinics and hired and trained at least 350 national staff. Wide-ranging community outreach, informational sessions, and messaging were conducted before and during the trial to ensure full communication to the population of the study area regarding procedures and current knowledge about the trial vaccine. During April 9-August 15, 2015, STRIVE enrolled 8,673 participants, of whom 453 and 539 were also enrolled in the safety and immunogenicity substudies, respectively. As of April 28, 2016, no Ebola cases and no vaccine-related serious adverse events, which by regulatory definition include death, life-threatening illness, hospitalization or prolongation of hospitalization, or permanent disability, were reported in the study population. Although STRIVE will not produce an estimate of vaccine efficacy because of low case frequency as the epidemic was controlled, data on safety and immunogenicity will support decisions on licensure of rVSV-ZEBOV.The activities summarized in this report would not have been possible without collaboration with many U.S. and international partners (http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/partners.html).

Association of Progestin Contraceptive Implant and Weight Gain.

OBJECTIVE: To evaluate initiation of a two-rod, 150-mg levonorgestrel contraceptive implant on women's perceived and observed body weight. METHODS: We conducted a secondary analysis of data from an open, randomized controlled trial of adult, nonpregnant, human immunodeficiency virus-negative women attending a public clinic in Kingston, Jamaica, who were assigned to initiate implant use either immediately or after a 3-month delay. The primary objective of the parent study was to assess the effect of initiation of the implant on the frequency of condom use. We compared study arms during follow-up using one-sided χ tests for differences in perceived weight gain and loss, one-sided Wilcoxon-Mann-Whitney tests for median gain in measured weight, and logistic regression with generalized estimating equations for risk of gaining greater than 2 kg. RESULTS: From 2012 to 2014, women were assigned to the implant (n=208) or delay arm (n=206). At 3 months, more women in the implant arm (15.3%) reported perceived weight gain than in the control arm (4.3%) (P=.01). Despite differences in perception, the implant and control arms did not differ significantly in median weight gain at 1-month (0.0 kg and 0.0 kg, respectively; P=.44) and 3-month visits (0.5 kg and 0.0 kg, respectively; P=.27). Study arms did not differ in risk of gaining greater than 2 kg (odds ratio 0.9, 95% confidence interval 0.6-1.3). CONCLUSION: We found no evidence of weight gain from short-term implant use. Through the power of the nocebo effect, the practice of counseling women to expect possible weight gain from initiating implant use could lead them to perceive weight gain even in its absence and contribute to the early discontinuation of this highly effective contraceptive method.

Effects of initiating a contraceptive implant on subsequent condom use: A randomized controlled trial.

OBJECTIVE: To evaluate whether initiation of a contraceptive implant, a method of long-acting reversible contraception, reduces condom use, as measured by a biomarker of recent semen exposure [prostate-specific antigen (PSA)]. STUDY DESIGN: We conducted a randomized controlled clinical trial in which 414 Jamaican women at high risk for sexually transmitted infections (STIs) attending family planning clinics received the contraceptive implant at baseline ("immediate" insertion arm, N=208) or at the end ("delayed" insertion arm, N=206) of a 3-month study period. Participants were tested for PSA at baseline and two follow-up study visits and were asked about their sexual activity and condom use. RESULTS: At baseline, 24.9% of women tested positive for PSA. At both follow-up visits, the prevalence of PSA detection did not significantly differ between the immediate versus delayed insertion arm [1-month: 26.1% vs. 20.2%, prevalence ratio (PR)=1.3, 95% confidence interval (CI)=0.9-1.9; 3-month: 25.6% vs. 23.1%, PR= 1.1, 95% CI=0.8-1.6]. The change in PSA positivity over the three study visits was not significantly larger in the immediate arm compared to the delayed arm (1-sided p-value of .15). CONCLUSIONS: Contraceptive implants can be successfully introduced into a population at high risk of unintended pregnancy and STIs without a biologically detectable difference in unprotected sex in the short term. This information strengthens the evidence to support promotion of implants in such populations and can help refine counseling for promoting and maintaining use of condoms among women who choose to use implants. IMPLICATIONS: Sex unprotected by a condom was not higher over 3 months in women receiving a contraceptive implant, compared with those not receiving the implant.

Recent trends in hepatic diseases during pregnancy in the United States, 2002-2010.

OBJECTIVE: While pregnancy-related severe liver disorders are rare, when they occur morbidity and mortality rates are increased for mothers and infants. The objective of this study was to examine the prevalence and trends of hepatic diseases during pregnancy hospitalizations from 2002 through 2010 in the United States. STUDY DESIGN: Hospital discharge data were obtained from the Nationwide Inpatient Sample, the largest all-payer hospital inpatient care database in the United States that provides nationally representative estimates. Pregnancy hospitalizations with the following diagnoses were identified: hepatitis B, hepatitis C, gallbladder disease/cholelithiasis, liver disorders of pregnancy, chronic/alcohol-related liver disease, biliary tract disease, and HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome. Age, insurance status, hospital location, and hospital region were compared among women with and without hepatic diseases using a χ(2) test. Trends in rates of pregnancy hospitalizations and mean charges were analyzed using multivariable logistic and linear regression, respectively. RESULTS: From 2002 through 2010 there were an estimated 41,479,358 pregnancy hospitalizations in the United States. Gallbladder disease and liver disorders of pregnancy were the most common hepatic diseases (rates = 7.18 and 4.65/1000 pregnancy hospitalizations, respectively). Adjusted rates and mean charges significantly increased for all hepatic diseases during pregnancy over the study period. All hepatic diseases were associated with significantly higher charges compared to all pregnancy hospitalizations. HELLP syndrome was associated with the highest mean charges. CONCLUSION: This large study among a representative sample of the US population provides valuable information that can aid policy planning and management of these hepatic diseases during pregnancy in the United States.

Safety of tenofovir during pregnancy for the mother and fetus: a systematic review.

Tenofovir disoproxil fumarate (TDF) safety during pregnancy has important public health implications. This review summarizes TDF safety during pregnancy, focusing on pregnancy outcomes, congenital anomaly risk, and other potential toxicities on neonates. Although information is limited, TDF appears to be safe during pregnancy. In 6 studies of human immunodeficiency virus type 1 (and/or hepatitis B virus)-infected women receiving TDF during pregnancy, adverse events were mild to moderate; none were considered to be TDF-related. Five studies that followed in utero TDF-exposed infants showed no increased risk of growth or bone abnormalities. One study showed slightly lower infant height at age 1 year, but the significance is unclear. The Antiretroviral Pregnancy Registry database, with 1800 pregnancies exposed to TDF in the first trimester, does not indicate increased congenital anomaly risk with TDF exposure. More evidence collected prospectively, ideally with bone density measurements and randomized trial design, will be optimal to determine the effects of antenatal TDF exposure on children's health.

Randomized controlled trial on the effectiveness of counseling messages for avoiding unprotected sexual intercourse during sexually transmitted infection and reproductive tract infection treatment among female sexually transmitted infection clinic patients.

BACKGROUND: The effectiveness of counseling messages to avoid unprotected sex during short-term treatment for curable sexually transmitted infections is unknown. METHODS: We randomized 300 female STI clinic patients 18 years or older with cervicitis and/or vaginal discharge in Kingston, Jamaica, in 2010 to 2011, to 1 of 2 counseling messages for their course of syndromic treatment: abstinence only or abstinence backed up by condom use. At a follow-up visit 6 days afterward, we collected vaginal swabs to test for prostate-specific antigen (PSA), a biological marker of recent semen exposure, and administered a questionnaire assessing sexual behavior. RESULTS: No differences were found in the proportions of women testing positive for PSA at follow-up in the abstinence-plus-condom group (11.9%) and abstinence-only group (8.4%) (risk difference, 3.5; 95% confidence interval, -3.5 to 10.5). There also was no significant difference in reporting of unprotected sex between groups. Reporting a history of condom use before enrollment significantly modified the effect of counseling arm on PSA positivity (P = 0.03). Among those reporting recent condom use, 10.3% in the abstinence-only arm and 4.8% in the abstinence-plus-condom arm tested positive for PSA. Conversely, among those not reporting recent condom use, 6.5% in the abstinence-only arm and 17.3% in the abstinence-plus-condom arm had PSA detected. CONCLUSIONS: We found no evidence to support the superiority of either counseling message. Post hoc analyses suggest that women with recent condom experience may benefit significantly more from abstinence-plus-condom messages, whereas women without such experience may benefit significantly more from abstinence-only messages. Providers should weigh individual condom use history when determining the most appropriate counseling message.

Contraception for individuals with sickle cell disease: a systematic review of the literature.

BACKGROUND: Women with sickle cell disease have an increased risk of pregnancy-related complications and need safe, effective contraceptive methods to prevent unintended pregnancy. STUDY DESIGN: We conducted a systematic review to examine the safety of hormonal and intrauterine contraceptive use among women with sickle cell disease. RESULTS: Eight articles met the inclusion criteria. The evidence was of fair to poor quality and suggested that progestin-only and combined hormonal contraception had no effect on frequency of sickle crises or other adverse events and no effect on hematologic parameters associated with sickle crises. No studies examined the risk of thromboembolism in combined hormonal contraceptive users with sickle cell disease. There was insufficient evidence to comment on the safety of intrauterine contraception. CONCLUSION: While data are limited, there is no evidence to suggest that hormonal contraceptive use among women with sickle cell disease is associated with an increased risk of clinical complications.

Effect of treatment assignment on intravaginal cleansing in a randomized study of the diaphragm with candidate microbicide.

BACKGROUND: Intravaginal cleansing may predispose women to adverse health outcomes and may interfere with the effectiveness and safety of female-initiated methods for preventing sexually transmitted infections (STIs). In a 4-week randomized study of 192 Malagasy sex workers, we evaluated associations between self-reported intravaginal cleansing and randomization assignment: diaphragm with viscous candidate microbicide gel (Acidform™, TOPCAD, Chicago, IL, licensed to Instead, Coppell, TX), diaphragm with placebo hydroxyethylcellulose gel (HEC, ReProtect LLC, Baltimore, MD), Acidform alone, or HEC alone. METHODS: Women were counseled to avoid intravaginal cleansing and were blinded to gel assignment. We evaluated changes in self-reported intravaginal cleansing across the study and assessed the effects of treatment assignment and covariates on frequent (more than once daily) intravaginal cleansing. Significant predictors in domain-specific models were evaluated in an all-domain multiple regression model. RESULTS: The proportion of women reporting intravaginal cleansing decreased from baseline (97%) to week 1 (82%) (p < 0.001). Self-reported frequent intravaginal cleansing decreased from baseline (87% to 56%) during the same time period (p < 0.001). In adjusted analyses, the Acidform-diaphragm group had 60% lower odds of frequent intravaginal cleansing during the study (odds ratio [OR] 0.4, 95% confidence interval [CI] 0.2-0.8) compared to the control group (HEC only). HEC-diaphragm and Acidform only users did not differ from controls. Living on the coast of Madagascar, not cohabiting, frequent intravaginal cleansing at enrollment, and high coital frequency predicted frequent intravaginal cleansing during follow-up. CONCLUSIONS: Gel characteristics and the diaphragm's presence likely influenced women's cleansing. Viscous gel delivered by a cervical barrier (such as a diaphragm) may minimize the likelihood of frequent intravaginal cleansing.

Prevention of mother-to-child transmission of HIV-1: the role of cesarean delivery.

The risk of mother-to-child transmission (MTCT) of HIV can be reduced through cesarean delivery prior to the onset of labor and prior to rupture of the membranes (elective cesarean delivery [ECD]). As a result of this evidence, the American College of Obstetricians and Gynecologists and the Department of Health and Human Services Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission developed guidelines recommending ECD for HIV-infected women with plasma viral loads of more than 1000 copies/mL. Since the release of the recommendations, an increase in ECD has been seen among HIV-infected women in the United States. This article discusses the evidence on efficacy of ECD, current recommendations in the United States, and risks and morbidity related to ECD. Although the benefit of ECD in preventing MTCT of HIV is substantial, some questions remain. Specifically, the benefit of ECD for women with very low viral loads or for women using combination antiretroviral regimens is unclear, as is the timeframe after onset of labor or rupture of membranes within which ECD will still confer preventive benefits.

Promoting continuous use as a strategy for achieving adherence in a trial of the diaphragm with candidate microbicide.

Women need more choices for protection from HIV and other sexually transmitted infections (STIs). We conducted a randomized 4-week study in Madagascar in preparation for a Phase III randomized controlled trial (RCT) of the diaphragm with a candidate microbicide for STI prevention. All participants completed quantitative surveys; half participated in a qualitative interview. We advised women to wear the diaphragm at all times except for daily cleaning (rather than inserting it before intercourse). The objective of this analysis was to determine whether women who followed this "continuous use" approach more often used the diaphragm for 100% of sex acts as compared with other women. If so, this would support advising continuous diaphragm use in the upcoming RCT. To meet our objective, we analyzed qualitative data thematically, developed a measure of continuous diaphragm use based on qualitative data, and used multiple regression to evaluate the measure's association with adherence to diaphragm use during 100% of sex acts. Women who wore the diaphragm continuously had 4 times higher odds of reporting diaphragm use during 100% of sex acts (OR: 4.6, 95% CI: 1.2, 24.0). If the diaphragm proves effective against STI, continuous use may help women achieve high levels of protection.